Kaposi sarcoma (KS) is the leading cancer in HIV+ persons in the US and world-wide. In some countries in Sub-Saharan Africa it is the most common cancer in the country. Unlike in the US both HIV+ men and women present with KS in South Africa. Crucial aspects of the biology and pathology of the KS tumor cell remain unknown. This represents a gap in our knowledge that prevents tumor-targeted therapies. Knowing the exact lineage and origin of the KS tumor cell is essential if we were to develop novel KS-specific therapies. These interventions, be it drugs or cytotoxic antibodies, must selectively target KS tumor cells and not the normal cells lining blood vessels in essential organs such as heart or kidney. Recent work from many groups found evidence for multiple cell types in KS and for multiple cell types that support KSHV replication: lymphatic endothelial cells (LEC), transdifferentiated vein endothelial cells (VEC), perictyes, mesenchymal cells akin to epithelial-mesenchymal transition (EMT) and stromal fibroblasts. In sum, 20 years after the discovery of KSHV, we still do not know exactly which cells make up a KS lesions, what the spectrum of KS lesions is, and if they respond differently to therapy. This R21 application seeks to address some of these questions through the Construction and analysis of a South African KS tissue microarray.